Minutes meeting June 17, 2021

Agenda:

news and announcements
report from safety group: thermal and mechanical indices

Summary

An update from all the focus groups was given after which the safety group showed a draft of their proposal about recommendations on thermal and mechanical safety followed by a discussion.

Attendance report (non-exhaustive)

Alexander Bystritsky
Andrew Thomas
Anton Fomenko
Axel Thielscher
Benjamin Kop
Bradley Treeby
Charles Caskey
Colette Reniers
Cristina Pasquinelli
Ellen Bubrick
Elly Martin
Ghazal Darmani
Hermes Kamimura
Jean-Francois Aubry
Jerome Sallet
John Snell
Keith Murphy
Kim Butts Pauly
Kyle Morrison
Lennart Verhagen
Marcus Kaiser
Mark Schafer
Markus Ulsberger
Mikhail Shapiro
Miriam Klein Flügge
Robert Chen
Robin Cleveland
Samuel Pichardo
Seung Schik
Yoo Siti Yaakub
Sjoerd Meijer
Steffen Tretbar
Takahiro Osada
Til Ole Bergmann
Tulika Nandi
Xingao Cheng
Yasuo Terao
Zhihai Qiu

Meeting proceedings

Lennart Verhagen: Reporting from safety will be the main topic of the meeting. If you have urgent matters please let us know in the beginning so we can take this into account. We usually have a round with all the expert groups to hear what has happened and to update each other, so let us start there.

Update Focus Groups

Bradley Treeby (planning): Same as last time, modelling intercomparison, talking about matrix, working with safety group.

Elly Martin (equipment): We have a document that we are doing final review on. This will be uploaded to the website when possible; working on details of suggestions for doing consistency checks.

Lennart Verhagen (reporting): No update.

Benjamin Kop (open): No update, you will receive an email when there is an update

Lennart Verhagen: Reminder to everyone: we are setting up the website, the goal is to be ready in September to be ready to publicly share FUN2021 and the educational course.

Kim Butts Pauly (FUN2021): 35 abstracts, 4 categories, reviewing, putting together educational course

Lennart Verhagen (FUN2021): if you want to join, e.g., help out for an educational course, that is always welcome. Please do get in touch with Kim or Lennart if you have any interest or ideas.

Til Ole Bergmann (practice): The guide is growing, we are making progress.

Presentation safety group

Jean-François Aubry

Disclaimer: this presentation is a draft and discusses ideas that are still in development.

Recommendations on thermal and mechanical safety.

We have a lot to discuss, so this summarises our thoughts. Today we are talking about Physical safety not neurophysiological safety (will be discussed later): i.e., mainly thermal and mechanical. How to translate TUS to clinics in a safe way, with a reasonable timeline: By building on existing guidelines. But what are the closest guidelines? We are close to imaging guidelines, discussing mostly diagnostic ultrasound.

Mechanical safety

For ultrasound imaging, a mechanical index less than 1.9 was introduced which shows no problem in terms of burst sonification. Typically the mechanical index is increased by 25% when using long pulses. How would this impact the work? How does a 25% increase compare to experimental cavitation thresholds? All were simulation, few experimental studies have been conducted in vivo (fewer in the brain). Three examples show all a higher MI than the diagnostic recommendation. There is no evidence of cavitation, nor mechanical lesion for MI values lower than 1.9

We need to determine where pulse intensity integral is maximum. Key issue: estimate the maximum peak rarefactional pressure for the setup.

Possibilities:

Measure MI in water (no skull): if 1.9 there is no need for further calculation. If not : see 2 and 3
Analytical model taking into account the two bone/tissue interfaces and bone attenuation
Numerical model

Looking forward to models proposed by the modelling group to help us for point 2 and 3. So, for example, an estimate for the maximum pressure in the brain.

Thermal safety-existing standards

Record thermal rise and investigate what is the thermal rise produced by the setup for skin safety. Also introduced to estimate thermal rise in tissues: FDA marketing clearance of diagnostic ultrasound systems and transducers. The thermal index (TI) can be estimated with a simple formula. Thermal rise (TR) depends on target tissue with three cases

Types of thermal index

Soft tissue thermal index (TIS or Tis)
Bone-at-focus thermal index (TIB or Tib)
Bone-at-surface or cranial thermal index (TIC or Tic)

There are ways to approximate these, with a formula with some assumptions. The formula can be demonstrative, use the output power of transducer, divide to equivalent aperture diameter at the skull surface and divide this by C~tic~

The time period over which to take the average power still needs some more discussion (entire stimulus duration)

Thermal safety

Thermal effects are not limited to the use of ultrasound

MRI: max temperature of tissue should be 39 degrees Celsius

AIMDs: max temperature rise of 2 °C

General consensus in biomedical engineering on recommendation to limit temperature rise 2 degrees Celsius. Our recommendations: no thermal damage has been reported when thermal rise is lower than 2°C.

How to provide an estimate of the max temperature rise (TR)

Numeric estimation: conservative calculation with approximations

Experimental estimates: thermocouple measurements on experimental models

Comment: based on the definition of TI, in theory if the thermal rise is less than 2, thermal index will be less than 3. We can have a thermal index slightly higher than 2 for a given time. If it’s a really short time it could be lower than 3. But the recommendation would still be a max temperature rise of 2.

Summary of first thoughts on mechanical and thermal safety

No evidence of cavitation, nor mechanical lesions for MI values less than 1.9

No evidence of thermal damage when thermal rise is lower than 2 °C at any time.

Next step, make sure that we are within our range

Key issue: estimate the maximum peak rarefactional pressure for the setup

Measure the MI in water (no skull): if MI <1.9 there is no need for further calculation. If not: see 2 and 3.
Analytical model taking into account the two bone/tissue interface and bone attenuation
Numerical model

Key issue: estimate maximum thermal rise

Analytical model to estimate TI
Numerical model to estimate thermal rise
Experimental estimation with phantoms

Discussion

Jean-François Aubry: This is just a draft, it seems simple to reach a consensus especially on MI. We currently observe, even with long pulses, that 1.9 MI shows no lesions. 2 °C temperature rise shows to be very safe.

Kim Butts Pauly: To add to this, this is not neurophysiological safety, efficacy, accuracy at focus, where there beam is, or reproducibility. This is about minimum safety.

Jean-François Aubry: Exactly, this is about the very minimum of safety. We are also not talking about repetitive pulsing. It is purely about, in the basis, not damaging any tissue.

Hermes Kamimura: Thank you JF Aubry for sharing this. My only concern is that we have seen benefits of using temperature increase and this appeared to be safe, so I was wondering why not search further. The numbers you give here are super safe, but I wonder if we are missing opportunities.

Jean-François Aubry: Some are using thermal rise as a statement that TUS is dangerous, which makes it hard to decide on.

Robin Cleveland: I think restrictions are reasonable. Most TUS experiments have been done in this region. When we are working with brain tissue, it’s good to play on the safe side. Based on the data today we should be able to get some effects within these restrictions of 2 °C.

Lennart Verhagen: What is proposed here is not restriction or limits. Below the guideline, there is no further evidence needed to suggest safety. Above the guideline, it will be in your hands and your approach. We are not a regulatory body that states limits, but rather we state consensus that below a certain limit there is no harm. We cannot account for all possibilities.

Hermes Kamimura: Totally agreed, however, if we generate a document that states that a thermal rise below 2 degrees Celsius is safe, if that limit is exceeded, we will get reviewers that say that we are not safe. We can use imaging guidance techniques and/or apply several feedback control loops that can control the temperature level instead of saying don’t use above that limit. If you don’t have a system that controls this, I agree that you can use the maximal thermal rise. My concern is that they say below 2 degrees thermal rise is neuromodulation while above is not.

Jean-François Aubry: I agree that as long as you think it’s safe you can go beyond the limits, with a feedback control loop or simulation. The current regulatory body gave a 2 degrees for AIMS and MR and we can use it. The regulation might change, also from MR, and we can benefit from this. And we are not a regulatory body anyway. But we want to have some regulations for ultrasound, it might come, but for now it’s a safe way to do it. We don’t want to prevent anyone from using a higher MI, but you have to make sure to look at the literature if it’s safe.

Alexander Bytristsky: It’s important to make more studies on this. We used post-operative tissue and cadavers to test this, to report the mechanical index where the thermal index starts.

Jean-François Aubry: We need more data, also on living tissues. This will help us better understand the energy limit/temperature limit/mechanical limit to move on to generate new data. We need a lot of data because it depends on many factors.

Alexander Bytristsky: If we publish we can say it’s minimal to be safe, next sentence, upper limits of safety is not explored. And of course we need more histological and thermal data.

Kim Butts Pauly: As Hermes said, if you have better calculations or measurements you should use them. If you don’t have this you could use the limits discussed today.

Seung Schik Yoo: We also have to think about the patient groups down the road, not only healthy patients. The 2 degrees seems to be a good conclusion also for the patients.

Lennart Verhagen: Would you suggest that there would be a time limit together with a certain raise of temperature?

Jean-François Aubry: Yes, it makes sense to me that it is a combination of temperature and duration (thermal dose) and if you can control the temperature over time, that’s a way to do it. I would like to understand both rational (duration) and FDA (TIC less than 6). That’s why we will come back to discuss more about this. That’s why there was a question mark in the proposal. It’s hard to find a limit in the thermal index.

Lennart Verhagen: For the thermal rise, if you always remain below 2 degrees temperature rise, you don’t need further evidence. But would it be possible to calculate the time average thermal index over whatever window you choose for your stimulation protocol.

Jean Francois Aurby: If the time window is exactly the length of one of the sonications, that is what the duty cycle is for, to decrease the average power and keep in mind this is already the case for diagnostic ultrasound and they average over this to make it safe.

Sueng Schik Yoo: Last time you said: 2 °C limit, any time, anywhere in the body do you think it is still valid?

Jean-Francois Aubry: It is recommended for modalities that exist. Of course I would never say that if at one point at 2 sec for 4 °Cit’s dangerous. But you do have to take extra attention and integrate so that it is not dangerous. Which you can do with the feedback control loop.

Sueng Schik Yoo: Less than 2 °C in the body is considered safe

Jean-Francois Aubry: Between 2-4 you can have thermal effects, you can take advantage of this, but it’s more difficult to give general recommendations about that. We need to make sure that we do not prevent from doing this, but clearly state when going above 2 degrees that you have to make sure what you are doing.

Jean-Francois Aubry: We did a literature study, we investigated all histology results on animals after ultrasound. We are currently looking to understand when lesions are there. Limits need to be investigated in both cadavers and living animals

Lennart Verhagen: Closing in on end time, so if anyone would like to add something please do.

Keith Murphy: Interest in proposing a new worst case scenario degeneration factor if there is a thin piece of bone.

Jean-Francois Aubry: Currently discussing with Brad to make models for the worst case scenario. But this is really hard. Worst case scenario with simple formula.

Pierre Pouget: Collect all data from literature, to see what are the values that do not show any lesions or any effect. Maybe data that does create some histology that they did not publish and contact these people for their parameters. It’s very common to show that no histology effect has been reported in published study, but maybe there exist some data that could constrain a model and some data.

Bradly Treeby (chat): The very worst case scenario would be to just use the FDA 0.3dB derating for soft tissue (ie don’t account for the skull at all).

**Lennart Verhagen **(chat): for mechanical index

Jean-Francois Aubry: I agree, if we can simulate what happened, that would be beneficial to anyone.

Lennart Verhagen: thank you for this presentation and it’s time to close up. Next step is to continue along these lines to establish a domain to set a safe line. Also noting how important it is to listen to everyone and every experience.

END OF MEETING

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